New Treatment Options for Bartter’s Syndrome
The New England Journal of Medicine
August 31, 2000 — Vol. 343, No. 9
Letter To the Editor:
Bartter’s syndrome is a major cause of congenital salt wasting. As a consequence of abnormal salt reabsorption in the thick ascending limb of Henle’s loop due to mutations in the luminal sodium-potassium-2-chloride cotransporter (antenatal Bartter’s syndrome type I), the luminal potassium channel (antenatal Bartter’s syndrome type II), or the basolateral chloride channel (classic Bartter’s syndrome type III), the activity of the renin-angiotensin-aldosterone system increases. (1) Prostaglandins increase as a consequence of volume contraction, and this increase may itself stimulate renin secretion. (2) Unfortunately, prostaglandins block salt reabsorption by mechanisms that are not yet fully understood. (1)
The clinical problems in patients with Bartter’s syndrome (e.g., prematurity, polyuria, dehydration, and growth retardation) are to a large extent caused by elevated levels of prostaglandins. Current treatment options include indomethacin, a nonselective cyclooxygenase (COX) inhibitor, but this drug has a broad range of side effects and therefore requires expensive monitoring. (3)
Selective and specific COX-2 inhibitors have recently become available. (4) This isoenzyme seems to be responsible for the elevated levels of inducible prostaglandins from the macula densa and the thick ascending limb of Henle’s loop. (5)
We treated a two-year-old girl who had Bartter’s syndrome type II (body weight, 7.4 kg, which is below the 3rd percentile; length, 74 cm, which is also below the 3rd percentile) with a balanced sodium diet and the COX-2 inhibitor rofecoxib (Vioxx), given in a dose of 6.25 mg (0.8 mg per kilogram of body weight) once daily. See the results in Table 1.
The excretion of renal prostaglandin (prostaglandin E2) and systemic prostaglandin (prostaglandin E-M) (determined with the use of gas chromatography-mass spectrometry by Dr. H. W. Seyberth, Marburg, Germany), sodium, potassium, creatinine, and aldosterone-18-glucuronide was measured in 24-hour urine specimens. By using simultaneous serum measurements, we calculated the rates of urinary fractional excretion of sodium and potassium.
The elevated value for the fractional excretion of sodium indicates an adequate salt supply; a normal value is less than 1 percent. The elevated value for the fractional excretion of potassium indicates the presence of hyperaldosteronism due to renal salt loss and is the main reason for hypokalemia in patients with Bartter’s syndrome. As a result of COX-2 inhibition by rofecoxib in our patient, renin and aldosterone-18-glucuronide were markedly reduced, the value for prostaglandin E-M became normal, and the value for prostaglandin E2 became nearly normal. The volume of urine decreased from 2100 to 1400 ml per day while the serum creatinine concentration remained constant (0.5 mg per milliliter). The patient was well, with increases of 0.9 kg in weight and 6 cm in height, within 16 weeks after the start of treatment with rofecoxib. There were no side effects, and the clinical benefit was durable.
We suggest that selected patients with Bartter’s syndrome be treated with COX-2 inhibitors.
Robert Kleta, M.D.
Candan Basoglu, M.D.
Eberhard Kuwertz-Broking, M.D.
Muenster 48149, Germany
2. Wolf K, Castrop H, Hartner A, Goppelt-Strube M, Hilgers KF, Kurtz A. Inhibition of the renin-angiotensin system upregulates cyclooxygenase-2 expression in the macula densa. Hypertension 1999;34:503-7.
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5. Traynor TR, Smart A, Briggs JP, Schnermann J. Inhibition of macula densa-stimulated renin secretion by pharmacological blockade of cyclooxygenase-2. Am J Physiol 1999;277:F706-F710.Print This Post